Cannabinoid receptor 2 activating antibodies: A promising therapeutic strategy for macrophage-driven...

Fibrotic diseases, often fueled by chronic inflammation, represent a major unmet medical need. A critical driver of this process is the activation of macrophages, which secrete pro-inflammatory cytokines and chemokines, leading to immune cell recruitment and collagen deposition by myofibroblasts. Agonizing the cannabinoid receptor 2 (CB2), expressed on macrophages, offers a potential therapeutic avenue to suppress this activation. Despite widespread interest in CB2 modulation, challenges remain in the development of small-molecule agonists, including insufficient specificity and poor drug-like properties. Antibodies are highly specific with favorable pharmacokinetics and bioavailability, but G-protein coupled receptor (GPCR) agonist antibodies have been difficult to discover. Herein, the first-in-class CB2 agonist antibodies, AB120 and AB150, are presented. These antibodies are CB2 specific, G-α biased, and effectively decrease the expression of macrophage activation markers and key pro-inflammatory cytokines, including IL-6, IL-1β and TNF-α. Furthermore, treatment of ex vivo human precision-cut liver slice with CB2 agonist antibodies both reduces inflammatory markers and decreases collagen expression reinforcing their potential as antifibrotic agents. Thus, these novel CB2-specific agonist antibodies may be effective for a range of fibrotic and inflammatory conditions driven by chronic macrophage activation and demonstrating the potential of GPCR antibody agonists to drug this challenging class of targets. SIGNIFICANCE STATEMENT: Fibrotic diseases, which are typically driven by chronic inflammation lack effective treatments. CB2 agonism modulates macrophage activation to reduce pro-inflammatory cytokines suggesting a novel therapeutic avenue, but small-molecule CB2 agonists have faced substantial limitations due to off-target effects. Herein, two novel CB2-specific agonist antibodies with potent anti-inflammatory and antifibrotic effects in vitro and in a human ex vivo liver fibrosis model are presented. These antibodies provide a promising new therapeutic strategy and highlight the advantages of antibodies as GPCR agonist drugs.